Acitretin, an aromatic analogue of retinoic acid, is useful in the treatment of hyperkeratotic skin diseases such as psoriasis. It is a member of the retinoid family, a group of compounds related to retinol (vitamin A). Chemically, acitretin is (all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid represented by the following Formula I

The tetraene side chain in acitretin exists in all -trans configuration. The synthesis of acitretin involves a number of steps to build the tetraene side chain and generally results in a complex mixture of unwanted cis-trans isomers along with the desired all-trans product. Hitherto known processes for the preparation of acitretin either give impure product or involve a large number of steps. Thus, they are commercially not viable as they give low yield and involve cumbersome purification steps.
Acitretin was disclosed for the first time in U.S. Pat. No. 4,105,681 which, inter alia, describes several synthetic methods for the preparation of acitretin. All of these employ Wittig reaction or its modifications such as Wittig-Horner procedure and give a mixture of stereoisomers. Our attempts at preparing acitretin of the desired purity by following the processes taught in Examples 1 to 3 of the '681 patent were unsuccessful. A similar Witting process has been illustrated in DE 2636879 (Example 6) to give only 47% of the all trans-isomer along with 51% of the 11-cis isomer, as an impurity.
Alternative synthetic routes have been reported in Spanish patent, ES 2028649 and Helv. Chim. Acta. 370 (1989) which also give a mixture of cis-trans isomers.
The synthesis of all trans-isomer exclusively has been attempted in recent years. One such process has been described in Zh. Org. Chim. 792 (1989) which involves large number of steps thereby giving very low overall yield. The synthetic procedures cited in Biorg. Khim. 541 (1988), Khim. Farm. Zh. 43(1994) and Russian Patent No. 2001903 involve column chromatography at the intermediate or penultimate stages of preparation of acitretin which renders them unattractive for operation on industrial scale.
In light of the above drawbacks in the prior art processes, there is a need for the development of a simple and efficient process for the preparation of desired all trans-isomer of 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid (acitretin) in high purity.